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  • Title: Activation of nuclear factor-kappa B pathway by simvastatin and RhoA silencing increases doxorubicin cytotoxicity in human colon cancer HT29 cells.
    Author: Riganti C, Doublier S, Costamagna C, Aldieri E, Pescarmona G, Ghigo D, Bosia A.
    Journal: Mol Pharmacol; 2008 Aug; 74(2):476-84. PubMed ID: 18463201.
    Abstract:
    Doxorubicin efficacy in cancer therapy is hampered by the dose-dependent side effects, which may be overcome by reducing the drug's dose and increasing its efficacy. In the present work, we suggest that the activation of the nuclear factor-kappaB (NF-kappaB) pathway and of nitric-oxide (NO) synthase increases the doxorubicin efficacy in human colon cancer HT29 cells. To induce NF-kappaB, we took into account the effect of doxorubicin itself and of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin; as NF-kappaB inhibitors, we chose the sesquiterpene lactones parthenolide and artemisinin. Simvastatin increased the NF-kappaB activity and NO synthesis, elicited the tyrosine nitration of the multidrug resistance-related protein 3, and enhanced the doxorubicin intracellular accumulation and cytotoxicity. Simvastatin potentiated the effect of doxorubicin on the NF-kappaB pathway and the inducible NO synthase expression. The effects of simvastatin were due to the inhibition of the small G-protein RhoA and of its effector Rho kinase. Parthenolide and artemisinin prevented all of the statin effects by inducing RhoA/Rho kinase activation. On the other hand, they did not reduce the NF-kappaB translocation and doxorubicin intracellular content when RhoA was silenced by small interfering RNA (siRNA). It is interesting that RhoA siRNA was sufficient to increase NF-kappaB translocation, NO synthase activity, doxorubicin accumulation, and cytotoxicity also in non-stimulated cells. Our results suggest that artemisinin, a widely used antimalarial drug, may impair the response to doxorubicin in colon cancer cells; on the contrary, simvastatin and RhoA siRNA may represent future therapeutic approaches to improve doxorubicin efficacy, reducing the risk of doxorubicin-dependent adverse effects.
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